Cholecystokinins (CCK) are neuropeptides which include CCK-33, a neuropeptide of thirty-three amino acids in its originally isolated form (see, Mutt and Jorpes, Biochem. J. 125. 678 (1971)), its carboxylterminal octapeptide, CCK-8 (a naturally-occurring neuropeptide, also, and the minimum fully active sequence), and 39- and 12-amino acid forms. CCK's are believed to be physiological satiety hormones and, therefore, may play an important role in appetite regulation (G. P. Smith, Eating and Its Disorders, A. J. Stunkard and E. Stellar, Eds., Raven Press, New York, 1984, p. 67).
Gastrin occurs in 34-, 17- and 14-amino acid forms in circulation and is related to CCK by identity of the C-terminal pentapeptides Gly-Trp-Met-Asp-Phe-NH.sub.2. Both gastrin and CCK exist in gastrointestinal tissue and in the central nervous system (see, V. Mutt, Gastrointestinal Hormones, G. B. J. Glass, Ed., Raven Press, N.Y., 1980, p. 169 and G. Nisson, ibid. p. 127).
Among additional effects, CCK's stimulate colonic motility, gall bladder contraction, pancreatic enzyme secretion, and inhibit gastric emptying. CCK's reportedly co-exist with dopamine in certain mid-brain neurons and thus may also play a role in the functioning of dopaminergic systems in the brain, as well as serving as neurotransmitters in their own right. See: A. J. Prange et al., "Peptides in the Central Nervous System", Ann. Repts. Med. Chem. 17, 31, 33 (1982) and references cited therein; J. A. Williams, Biomed. Res. 3 107 (1982); and J. E. Morley, Life Sci. 30, 479, (1982). The primary role of gastrin appears to be stimulation of the secretion of water and electrolytes from the stomach, and, as such, it is involved in control of gastric acid secretion.
Antagonists to CCK have been useful for preventing and treating CCK-related disorders of the gastrointestinal, central nervous and appetite regulatory systems of animals, especially of humans. CCK antagonists are also useful in potentiating and prolonging opiate-mediated analgesia and thus have utility in the treatment of pain [see P. L. Faris et al., Science 226, 1215 (1984)]. Gastrin antagonists are useful in the treatment and prevention of gastrin-related disorders of the gastrointestinal system in humans and animals, such as ulcers, Zollinger-Ellison syndrome, antral G cell hyperplasia and other conditions, in which reduced gastrin activity is of therapeutic value. CCK and gastrin also have trophic effects on certain tumors [K. Ohyama, Hokkaido J. Med. Sci., 60, 206-216 (1985)], and antagonists of CCK and gastrin are useful in treating these tumors [see, R. D. Beauchamp et al, Ann. Surg., 202, 303 (1985)].
Three distinct chemical classes of CCK-receptor antagonists have been reported. The first class comprises derivatives of cyclic nucleotides, of which dibutyryl cyclic GMP has been shown to be the most potent by detailed structure-function studies (see, N. Barlos et al., Am. J. Physiol,. 242, G 161 (1982) and P. Robberecht et al., Mol. Pharmacol. 17, 268 (1980)). The second class comprises peptide antagonists which are C-terminal fragments and analogs of CCK, of which both shorter (Boc-Met-Asp-Phe-NH.sub.2, Met-Asp-Phe-NH.sub.2), and longer (Cbz-Tyr(SO.sub.3 H)-Met-Gly-Trp-Met-Asp-NH.sub.2) C-terminal fragments of CCK can function as CCK antagonists, according to recent structure-function studies (see, R. T. Jensen et al., Biochem Biophys. Acta., 757, 250 (1983, and M. Spanarkel et al.. J. Biol. Chem., 258, 6746 (1983)). The latter compound was recently reported to be a partial agonist [see, J. M. Howard et al., Gastroenterology 86(5) Part 2, 1118 (1984)]. Then, the third class of CCK-receptor antagonists comprises the amino acid derivatives: proglumide, a derivative of glutaramic acid, and the N-acyl tryptophans including para-chlorobenzoyl-L-tryptophan (benzotript), [see, W. F. Hahne et al., Proc. Natl. Acad. Sci. U.S.A., 78, 6304 (1981l ), and R. T. Jensen et al., Biochem. Biophys. Acta., 761, 269 (1983)]. All of these compounds, however, are relatively weak antagonists of CCK (IC.sub.50 : generally 10.sup.-4 M (although more potent analogs of proglumide have been recently reported in F. Makovec et al., Arzneim-Forsch Drug Res., 35 (II), 1048 (1985) and in German Patent Application DE 3522506Al), but down to 10.sup.-6 M in the case of peptides), and the peptide CCK-antagonists have substantial stability and absorption problems.
In addition, improved CCK-antagonists comprising a nonpeptide of novel structure from fermentation sources [R. S. L. Chang et al. Science, 230, 177-179 (1985)]and 3-substituted benzodiazepines based on this structure [published European Patent Applications 0 167 919, 0 167 920 and 0 169 392] have also been reported.
No really effective receptor antagonists of the in vivo effects of gastrin have been reported (J. S. Morley, Gut Pept. Ulcer Proc., Hiroshima Symp. 2nd, 1983, p. 1), and very weak in vitro antagonists, such as proglumide and certain peptides have been reported [J. Martinez, J. Med. Chem. 27, 1597 (1984)]. Recently, however, pseudopeptide analogs of tetragastrin have been reported to be more effective gastrin antagonists than previous agents [J. Martinez et al., J. Med. Chem., 28, 1874-1879 (1985)].
It was, therefore, an object of this invention to identify substances which more effectively antagonize the function of cholecystokinins in disease states in mammals, especially in humans. It was another object of this invention to prepare novel compounds which inhibit cholecystokinins and antagonize the function of gastrin. It was still another object of this invention to develop a method of antagonizing the functions of cholecystokinin/ gastrin in disease states in mammals. It is also an object of this invention to develop a method of Preventing or treating disorders of the gastrointestinal, central nervous and appetite regulatory systems of mammals, especially of humans.